C4 Flashcards
Antifungal drugs?
9
- Clot.RimaZol (ريما)
- Fluconazol
- Itraconazol
- Voriconazol
- Caspofungin (فنجان)
- Flucytosin
- Terbinafine
- Nystatin
- Amphotericin B
what about Amphotericin B?
Amphotericin B is a polyene Abx related to nystatin
Amphotericin B PharmacoKinetix?
- administered I.V. in 3 forms poorly (absorbed from G.I.T)
1. nonlipid colloidal suspension
2. lipid complex
3. liposomal formulation (less nephrotoxic) - IV for systemic infection
- topical for ocular/bladder infections
- distribution: all tissues (except CNS)
- Elimination: slow hepatic metabolism
( a bit in urine) - 1/2 life: ± weeks
-
Amphotericin MOA?
- fungicidal
- affect the permeability and transport properties of fungal membranes
- bind to Ergosterol (cell membranes) –> leaky pores
- Resistance: uncommon, occurs if membrane ergosterol level or structure decrease
Amphotericin B Clinical uses?
- used for initial induction regimens before Azole
- widest Antifungal spectrum
- drug of choice, or codrug of choice, for most systemic mycosis infection caused by (Aspergillus, Candida , Cryptococcus, histoplasma)
- given by slow I.V.
Amphotericin Toxicity?
Nephrotoxicity is dose limiting
Neurotoxicity
infusion rxn ( chills, fever, muscle spasm, hypotension)
Amphotericin B I.V. Infusion related toxicity?
- fever
- chills
- muscle spasms
- vomiting
- hypotension (shock-like fall in blood pressure)
- effects can be attenuated by: slow infusion rate and premedication with antihistamines, antipyretics, glucocorticoids*
Amphotericin B dose limiting toxicity?
- decreases the GFR + RTA renal tubular acidosis (with magnesium and potassium wasting)
- Anemia: decrease of erythropoietin formation
- Liposomal formulations have reduced nephrotoxic effects
Amphotericin B Neurotoxicity toxicity?
Intrathecal administration –> seizures and neurologic damage
what about Flucytosine?
pyrimidine antimetabolite related to the anticancer 5-FU
Flucytosin PharmacoKinetix?
- Bioavailability: effective orally
- distribution: most body (also CNS)
- Elemination: intact in the urine
(dose must be reduced in patients with renal impairment)
Flucytosine MOA?
Inhibits DNA , RNA polymerases
- membrane permease –> accumulate the drug in fungal cells –> converted by cytosine deaminase to –> 5-FU –> inhibits thymidylate synthase
- Resistance can occur rapidly if flucytosine is used alone
- When 5-FC is given with amphotericin B/ itraconazole –> emergence of resistance is decreased and synergistic antifungal effects may occur
Flucytosine clinical uses?
- antifungal spectrum of 5-FC is narrow
- limited to the treatment in combination with amphotericin B / itraconazole
- used against:
1. synergistic with Amphotericin B in Candidemia , cryptococcus neoformans
2. molds (for chromoblastomycosis)
Flucytosine Toxicity?
- Prolonged high plasma LvLs:
1. reversible bone marrow depression
2. alopecia
3. liver dysfunction.
Azole Antifungal agents?
FIV(5)
- Fluconazol
- Itraconazol
- Voriconazol
- Clotrimazole
Azoles MOA
- inhibit fungal P450 dep- enzymes blocking ergosterol synthesis –> interfere with membrane permeability
- resistance with long-term use azoles (long-term prophylaxis in immunocompromised and neutropenics)
Azoles PharmacoKinetix?
- Bioavailability: orally absorbed
- distribution: most body tissues
(fluconazole has excellent CNS penetration (fungal meningitis) - metabolism and elimination:
- -> Liver for Itra, Vori, clotrimazole
- -> kidney for Fluco (unchanged in urine)
Fluconazole clinical uses?
- Blastomycosis
- alternative drug in candidemia and infections caused by aspergillus, blastomyces, cryptococcus, histoplasma
- treatment and secondary prophylaxis against cryptococcal meningitis (bcz excellent CNS penetration)
- Esophageal and Oropharyngeal candidiasis and most infections by Coccidioides
- A single oral dose usually eradicates vaginal candidiasis
- alternative drug (with amphotericin B) in active Cryptococcus neoformans
Itraconazole clinical uses?
- systemic infections:
Blastomycosis and Sporothrix - alternative agent against Aspergillus, Coccidioides, Cryptococcus
Esophageal candidiasis - subcutaneous chromoblastomycosis
- used in dermatophytoses (especially onychomycosis)
Voriconazole clinical uses?
- wider spectrum than itraconazole
- against invasive aspergillosis
- alternative drug in candidemia
- in AIDS patients: candidal esophagitis and stomatitis
Azoles Toxicity?
- vomiting
- diarrhea
- rash
- hepatotoxicity (preexisting liver dysfunction)|
- Voriconazole causes immediate but transient visual disturbances including blurring of vision of unknown cause in more than 30% of patients
+ CLASS D risk in pregnancy
Echinocandins example?
Caspofungin
what about Caspofungin ?
echinocandin
Caspofungin pharmacoKinetix?
- Bioavailability: I.V.
- distribution: widely to the tissues
- elimination: hepatic metabolism
- 1/2 life: 9–12h
Caspofungin MOA?
- fungicidal
- inhibits Beta-glucan synthase –> inhibits synthesis of beta-Glucan (fungal cell walls)
Caspofungin Clinical uses?
- used for disseminated and mucocutaneous Candida infections
- salvage therapy in aspergilosis
- mucormycosis
- used after fail to respond to amphotericin B*
caspofungin Toxicity?
- well tolerated
- Infusion-related:
1. Hepatotoxicity
2. G.I.T distress
3. fever
4. rash
5. flushing (histamine release)
6. headahce
Combined use of echinocandins with cyclosporine may elevate liver transaminases
Terbinafine MOA?
- fungicidal
- inhibit epoxidation of squalene –> accumulation of toxic levels of squalene–> interfere with ergosterol synthesis
Terbinafine Clinical uses?
- oral (DOA: weeks ). / topical
- accumulates in keratin
- used in muco-cutaneous fungal infections.
- effective in onchomycosis
Terbinafine Toxicity?
- G.I.T. upsets
- rash
- headache
- taste disturbances
Topical Antifungal?
Nystatin
what about Nystatin?
- polyene antibiotic
- used topically for superficial infections caused by Candida and dermatophytes
Nystatin MOA?
disrupts fungal membranes by binding to ergosterol
Nystatin MOA?
disrupts fungal membranes by binding to ergosterol
Nystatin clinical uses?
- topically: suppresses local Candida infections
- orally: eradicates GI fungi (if impaired defense)
Nystatin clinical uses?
- topically: suppresses local Candida infections
- orally: eradicates GI fungi (if impaired defense)
